S4-3 Novel pharmacological tools for the H2S pathway

Abstract

Hydrogen sulfide (H2S) regulates smooth muscle tone, cell metabolism and growth, apoptosis and migration. It has, thus, been implicated in a plethora of physiological and pathophysiological processes including angiogenesis, cardioprotection, atherosclerosis, inflammation and cancer. H2S is produced by cystathionine beta synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST). Aminoethoxyvinylglycine (AVG), β-cyano- l -alanine (BCA) and propargylglycine (PAG) selectively inhibit CSE over CBS and 3-MST. All of them, exhibit limited potency and block other PLP-dependent enzymes, too. It should be emphasized that no selective CBS or 3-MST inhibitors are currently available. During this presentation data obtained from a screen of chemical libraries against H2S-synthesizing enzymes will be presented. The available donors can be divided based on their chemical nature and rate of release to inorganic vs organic compounds and fast vs slow releasers. The most widely used inorganic compounds to generate H2S are NaSH and Na2S. These compounds dissociate rapidly in solution leading to immediate H2S formation. The organic donors available can be divided according to their source of origin into naturally occurring and synthetic. Contrary to inorganic salts, the organic donors release H2S more slowly; the rate of H2S liberation may differ substantially depending on the absence or presence of biological material. Mitochondrial-targeted donors and hybrid molecules between known drugs and H2S-releasing moieties are special subclasses of H2S donors. During the second part of the presentation data on signalling, pharmacological profiles and biological activities in the context of cardiovascular disease of different classes of H2S-generating compounds will be analysed.